Actions of picrotoxinin analogues on an expressed, homo-oligomeric GABA receptor of Drosophila melanogaster.

The actions of picrotoxinin and four of its analogues were tested on a Drosophila melanogaster homo-oligomeric GABA (gamma-aminobutyric acid) receptor formed when RDL (resistance to dieldrin) subunits were expressed in Xenopus oocytes. In agreement with previously reported studies on native insect GABA receptors and native expressed vertebrate GABA receptors, acetylation of the bridgehead hydroxyl group (picrotoxinin acetate) greatly reduced the activity of the molecule, but surprisingly, substitution with flourine at the same position also reduced the activity. Conversion of the terminal isopropenyl group to an acetyl (alpha-picrotoxinone) or hydration of the double bond (picrotin) also reduced activity, in agreement with findings for native insect and mammalian receptors. The present results suggest that interactions of convulsants with homo-oligomeric and multimeric GABA receptors are qualitatively similar. Thus, the RDL homo-oligomer exhibits a pharmacological profile for picrotoxinin analogues resembling that of native GABA receptors.